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According to the 2022 World Health Organization (WHO) classification, NENs are categorized into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, with NETs further subdivided into G1, G2, and G3 according to the Ki-67 index. Among these, gastroenteropancreatic NENs (GEP-NENs) account for most cases and have become an important area of therapeutic investigation. As understanding of the disease has deepened, various treatment modalities have been developed, and treatment strategies tailored to specific subtypes have become increasingly complex. Currently, the treatment selection for GEP-NENs is largely based on the WHO classification. Hormonal therapy, molecular-targeted therapy, cytotoxic chemotherapy, and peptide receptor radionuclide therapy are standard treatment options for unresectable GEP-NETs, whereas cytotoxic chemotherapy remains the standard of care for GEP-NECs. However, therapeutic development and clinical outcomes remain unsatisfactory in unresectable NENs because of their rarity, highlighting the need for further therapeutic advancements in systemic therapy. In this review, we summarize the current landscape of systemic therapies, recent therapeutic advances, and their underlying biological mechanisms in GEP-NENs, while discussing the ongoing challenges and future directions in the field.<\/jats:p>","DOI":"10.1177\/17588359261471127","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:51:33Z","timestamp":1785156693000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Systemic therapy for gastroenteropancreatic neuroendocrine neoplasms: current landscape and future directions"],"prefix":"10.1177","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2212-9049","authenticated-orcid":false,"given":"Eiichiro","family":"So","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku Tokyo, Japan"},{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Minato, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chigusa","family":"Morizane","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Okusaka","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2025.15798","article-title":"Epidemiology of neuroendocrine neoplasms in the US","volume":"8","author":"Dasari A","year":"2025","unstructured":"Dasari A, Wallace K, Halperin DM, et al. 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